We propose to confirm and extend our observations that susceptibility to phenytoin-induced cleft palate in inbred strains of mice is regulated by a gene in or near the H-2 histocompatibility locus. Binding of 3H-phenytoin will be studied in palatal tissue of sensitive strains of mice by conventional techniques and by our micromethods and compared to that in resistant strains. Phenytoin and other cleft palate teratogen receptors will also be sought in palatal and skin fibroblast cultures of infants with and without cleft palates with the hope that receptor levels can be shown to be a controlling factor in human cleft palate. In humans phenytoin has been associated with cleft lip and cleft palate. If phenytoin is given at an early stage in mice, it also produces cleft lip. We also propose to include the study of phenytoin-induced cleft lip and palate in mice as a model of the fetal phenytoin syndrome. Phenytoin can form a reactive epoxide intermediate which may be related to its teratogenicity. The known differences in mixed function oxidase enzyme system in cleft palate susceptible and resistant strains of mice may account for the formation of this intermediate which may covalently bind to target tissues at a critical period. We would also like to determine whether phenytoin inhibits programmed cell death as a major factor in its teratogenic effect. In short, we hope to delineate the molecular chain of events involved in the action of a teratogenic drug in both animals and humans with cleft (lip) palate as a model of drug-induced craniofacial anomalies.